The present invention relates to a process for producing fast-setting, bioresorbable calcium phosphate cements (CPC), and in particular, to a process including a pre-heat treatment step to generate uniformly distributed submicron-sized apatite seeds.
Due to its superior biocompatibility and osteoconductivity, CPC has been used as implant or filling material in dental or bone prosthesis and the like (Chow et al., 1991;Chohayeb et al., 1987: Costantine et al., 1991j; Firedman et al; Hong et al; 1991; Sugawara et al., 1992; Hamanish et al; 1996). In 1983, Brown and Chow indicated that mixing tetracalcium phosphate (TTCP) and dicalcium phosphate anhydrous (monetite) (DCPA) powder to obtain a powder mixture and mixing the powder mixture in a diluted phosphate-containing solution can obtain hydroxyapatite (HA). Implants made from thus produced HA have a compressive strength up to 51 MPa. However, in application, the setting time is too long (for example, 30 minutes) and the mechanical properties are still inferior compared to enamel, tooth and metal composite. Moreover, as the setting time is long, the material can be flushed away by body fluid/blood before it is set.
A great deal of effort has been expended to solve the long setting time problems. U.S. Pat. No. 4,959,104 provides a process for producing a fast-setting CPC which becomes set within several minutes. Inorganic fluorides, such as CaF2, MgF2 and BeF2 are added to increase the compressive strength of the CPC. NaF, LiF or KF is added in the organic acid or inorganic acid solution to shorten the setting time to form a stable apatite type product.
U.S. Pat. No. 5,092,888 provides a hardening material comprising (1) a powder component composed of a powdery mixture of tetracalcium phosphate and calcium phosphate having a Ca/P atomic ratio lower than 1.67 and (2) a liquid component composed of a colloidal aqueous solution comprising solid colloid particles dispersed in an aqueous medium.
U.S. Pat. No. 5,180,426 provides a calcium phosphate type setting material comprising (1) powder comprising at least one of xcex1-tricalcium phosphate and tetracalcium phosphate; and (2) a setting solution comprising an aqueous acidic solution having dissolved therein at least one polysaccharide selected from the group consisting of carboxymethyl chitin, glycol chitin, pullalan, high methoxy-pectin and chitosan.
U.S. Pat. No. 5,262,166 provides a surgical cement comprising a calcium alkali phosphate cement with relatively high surface pH of about 7 or higher. In the calcium alkali phosphate cement, citric acid, acidic citrate salts are added as setting agent and CaO, Na2O, P2O5, MgO and collagen are added to shorten the setting time.
U.S. Pat. Nos. 5,336,264 and 5,820,632 show that setting times of calcium phosphate cement compositions are enhanced by the addition of sodium phosphate or sodium carbonate lubricant compositions.
U.S. Pat. No. 5,525,148 provides a composition relating to calcium phosphate cement that self-hardens substantially to hydroxyapatite at ambient temperature when in contact with an aqueous medium. Phosphates such as Na3PO4, Na2HPO4 and NaH2PO4 are added in the composition.
As discussed above, these approaches use metal ion-containing compounds, polymeric compounds or collagens as the setting agents to improve the long setting time problem. Metal ions in setting agents may cause diseases when applied in vivo. Some evidence shows that aluminum ions might be associated with peripheral neuropathy, osteomalacia and aizheimer diseases; vanadium ions can cause cytotoxicity; Ni and Cr compounds may cause cancer; and Ni or Cr metal ions can induce the immunological sensitization of human beings. Although titanium and titanium alloys are considered bio-compatible, it was recently reported that scraps of titanium alloys may also cause detrimental reactions to the vicinal living tissues or cause cytotoxicity (K. Soballe, xe2x80x9cHydroxyapatite ceramic coating for bone implant fixationxe2x80x9d, ACTA Orthopaed. Scandin Supplem., 64:1-58, 1993; J. J. Callaghan, Current concerts review, xe2x80x9cThe clinical results and basic science of total hip arthroplasty with porous-coated prostheresxe2x80x9d J. Bone Joint Surg., 75A: 299-310, 1993). Polymeric compounds may degrade into their monomers which are also detrimental biologically. While collagens are biocompatible, their dissolution rates are usually too high and found practically inconvenient.
Bioresorbable materials have advantages when being used in medical implants. Bioresorbable materials will be gradually degraded when they are implanted in animals or humans, thus allowing replacement by new bone growth.
U.S. Pat. No. 5,053,212 discloses the production of a bioresorbable hydroxyapatite. A dry mixture is first provided in which TTCP and ortho-phosphoric crystals, monocalcium phosphate monohydrate are combined with mechanical mixing to control the Ca/P ratio to approximately 1.25-2.0:1. The dry mixture is then mixed with water or polyols or ethylene glycol to obtain the bioresorbable hydroxyapatite.
U.S. Pat. No. 5,149,368 provides a process for the preparation of bioresorbable calcium phosphate cement. The process uses decomposable tricalcium phosphate and tetracalcuim phosphate as main ingredients and undecomposable hydroxyapatite as secondary ingredients. These ingredients are intensively mixed with setting agents, i.e., acidic citrate, to obtain a mixture and the mixture is then mixed with an appropriate solvent to obtain a slurry. NaOH, KOH or NH4OH is added to adjust the pH to greater than 5. Antibiotics and bone morphological proteins are also added. The resultant calcium phosphate cements are biocompatible, bioresorbable and have satisfactory working time.
U.S. Pat. No. 5,342,441 provides a biocompatible composition which includes a powder component containing Ca4P2O9 and at least one of CaHPO4 and CaHPO4H2O at a molar ratio of Ca:P of 1.16-1.95; and a liquid component containing 1 mM to 2M of a second phosphate ion and 1 mM to 2M of an organic ion. The biocompatible material converts into hydroxyapatite when being implanted into human or animals and a part thereof can be replaced by newly grown bones.
U.S. Pat. No. 5,503,164 provides a method for the repair of craniomaxillofacial bony defects using a low temperature-hardening, gradually resorbable hydroxyapatite forming cement. The resorbable hydroxyapatite forming cement is obtained by adding some bio-dissolvable salts such as silicate acrylic salts.
U.S. Pat. Nos. 5,542,973, 5,545,254 and 5,695,729 provide a composition comprising tetracalcium phosphate which has been prepared from a mixture with a calcium to phosphorous ratio of less than 2 under substantially anhydrous or vacuum conditions and which is converted substantially to hydroxyapatite upon setting.
U.S. Pat. No. 5,814,681 provides a restorative composition for hard tissue, comprising a paste (A) containing an inorganic calcium phosphate powder, a polymerizable monomer mixture and a polymerization initiator, and a paste (B) containing an inorganic calcium phosphate powder, a polymerizable monomer mixture and a polymerization accelerator.
However, these processes for producing biodegradable compositions use expensive additives or require a complicated procedure, such as being conducted in a vacuum or a water-free ambient.
It is therefore an object of the invention to provide simple, inexpensive and easy to control process for producing a fast-setting biocompatible, bioresorbable calcium phosphate cement.
The invention accomplishes the above object by providing a process comprising the following steps: obtaining a powder mixture from at least one calcium phosphate selected from the group consisting of Ca4(PO4)2O, CaHPO4 2H2O, CaHPO4, Ca8H2(PO4)6 5H2O, xcex1-Ca3(PO4)2, xcex2-Ca3(PO4)2, Ca2P2O7, Ca2H2P2O8, wherein the molar ratio of Ca to P in the mixture is roughly between 1 and 2; mixing the powder mixture in a phosphate-containing solution to obtain a powder/solution mixture having a concentration of less than 4 g powder mixture per 1 ml solution; immediately heating the powder/solution mixture to a temperature of roughly 50xc2x0 C.-350xc2x0 C. to obtain a powder containing uniformly distributed submicron-sized apatite crystals; and mixing the apatite crystal-containing powder in a phosphate ion-containing solution to obtain a fast-setting, bioresorbable calcium phosphate cement.
The process can further include adding approximately 3% by weight of additional phosphate or fluoride-containing compounds to the phosphate ion-containing solution in the step of mixing the apatite crystal-containing powder in a phosphate ion-containing solution to increase the bio-activity of the resulting CPC.
The present invention also provides a fast-setting, bioresorbable calcium phosphate cement prepared by the above described process. In addition, the present invention provides a composite comprising a fast-setting, bioresorbable calcium phosphate cement prepared by the above described process and at least one other bioresorbable powder, for example calcium phosphate powder or bioactive glass powder. The composite can either be in the form of a matrix of CPC into which the bioresorbable powder is interspersed or alternating layers of CPC and bioresorbable powder.
The process of this invention is simple and the parameters are easy to control. By using a pre-heat treatment to generate apatite seeds, the seeds are more uniformly distributed than when externally added because powder aggregation can be avoided, and seed size can be easily controlled to meet different applications. Furthermore, the internally nucleated seeds are more biocompatible than other added seeds (for example, Al2O3), and can be easily combined with calcium phosphate, collagens, and bioresorbable polymer. dr
The following detailed description, given by way of examples and not intended to limit the invention to the embodiments described herein, will best be understood in conjunction with the accompanying drawings, in which:
FIG. 1 shows a temperature profile for heating the powder mixture of Ca2P2O7 and CaCO3 in the preparation of TTCP powder in preparative example 1;
FIG. 2 shows the compressive strengths of the fast-setting, bioresorable CPC specimens after being immersed in Hank""s solution for a variable number of days;
FIG. 3 shows the compressive strengths of the fast-setting, bioresorable CPC specimens obtained from the CPC powder which is heated to a variable temperatures;
FIG. 4 shows pH values of the fast-setting, bioresorable CPC pastes obtained from the powders which were heated to 50xc2x0 C., 100xc2x0 C. and 150xc2x0 C. in Example 3;
FIG. 5 shows the X-ray diffraction patterns of the conventional CPC specimen, the non-dissolvable, fast-setting CPC specimen and the fast-setting, bioresorbable CPC specimen in Example 4, wherein A represents the X-ray diffraction pattern of the conventional CPC specimen immersed in Hank""s solution for 7 days, B represents the X-ray diffraction pattern of the non-dissolvable, fast-setting CPC specimen immersed in Hank""s solution for 7 days, C represents the X-ray diffraction pattern of the fast-setting, bioresorbable CPC specimen immersed in Hank""s solution for 1 day, and D represents the X-ray diffraction pattern of the fast-setting, bioresorbable CPC specimen immersed in Hank""s solution for 7 days;
FIG. 6a is a bright field transmission electron micrograph of the fast-setting, bioresorbable CPC powder prepared from the preparative example 2;
FIG. 6b is a dark field transmission electron micrograph of the same area in FIG. 6a;
FIG. 6c is a picture showing the selected area electron diffraction pattern of the same area of the same powder prepared from preparative example 2;
FIG. 7 is schematic drawing showing a composite consisting of the fast-setting, bioresorbable CPC of the invention and other bioresorbable material being used as the implant of a dental root socket; and
FIG. 8 is a schematic drawing showing an alternative embodiment of a composite consisting of the fast-setting, bioresorbable CPC of the invention and other bioresorbable material being used as the implant of a dental root socket.